5-(4phenyl)prolinamide for treatment of epilepsy

ABSTRACT

The invention provides a compound of formula (I), a solvate, a salt or prodrug thereof, 
     
       
         
         
             
             
         
       
     
     useful in the treatment of diseases and conditions mediated by modulation of use-dependent voltage-gated sodium channels.

This application is a Continuation of U.S. application Ser. No.11/570,560 filed Dec. 13, 2006, now allowed; which was filed pursuant to35 U.S.C. §371 as a U.S. National Phase Application of InternationalPatent Application No. PCT/EP06/09731 filed Oct. 6, 2006, which claimspriority from Great Britain Application No. GB 0520581.0 filed Oct. 10,2005 and from Great Britain Application No. 0523045.3 filed Nov. 11,2005 in the United Kingdom.

The present invention relates to an α-aminocarboxyamide derivative,salts and prodrugs thereof, and to the use of this derivative, salts andprodrugs thereof in treating diseases and conditions mediated bymodulation of use-dependent voltage-gated sodium channels. In addition,the invention relates to compositions containing this derivative, saltsand prodrugs thereof, and processes for their preparation.

Voltage-gated sodium channels are responsible for the initial phase ofthe action potential, which is a wave of electrical depolarisationusually initiated at the soma of the neuron and propagated along thenerve axon to the terminals. At the terminals, the action potentialtriggers the influx of calcium and the release of neurotransmitter.Drugs, such as lidocaine, that block voltage-gated sodium channels areused as local anaesthetics. Other sodium channel blockers, such aslamotrigine and carbamazepine are used to treat epilepsy. In the lattercase, partial inhibition of voltage-gated sodium channels reducesneuronal excitability and reduces seizure propagation. In the case oflocal anaesthetics, regional block of sodium channels on sensory neuronsprevents the conduction of painful stimuli. A key feature of these drugsis their use-dependent mechanism of action. The drugs are thought tostabilise an inactivated configuration of the channel that is adoptedrapidly after the channel opens. This inactivated state provides arefractory period before the channel returns to its resting (closed)state ready to be reactivated. As a result, use-dependent sodium channelblockers retard the firing of neurons at high frequency, for example inresponse to painful stimuli, and will help to prevent repetitive firingduring periods of prolonged neuronal depolarisation that might occur,for example, during a seizure. Action potentials triggered at lowfrequencies, for example in the heart, will not be significantlyaffected by these drugs, although the safety margin differs in eachcase, since at high enough concentrations each of these drugs is capableof blocking the resting or open states of the channels.

The voltage-gated sodium channel family is made up of 10 subtypes, fourof which are brain specific, NaV1.1, 1.2, 1.3 and 1.6. Of the othersubtypes, NaV1.4 is found only in skeletal muscle, NaV1.5 is specific tocardiac muscle, and NaV1.7, 1.8, and 1.9 are found predominantly insensory neurons. The hypothesised binding site for use-dependent sodiumchannel blockers is highly conserved between all the subtypes. As aresult, drugs such as lidocaine, lamotrigine and carbamazepine do notdistinguish between the subtypes. However, selectivity can be achievedas a result of the different frequencies at which the channels normallyoperate.

Drugs that block voltage-gated sodium channels in a use-dependent mannerare also used in the treatment of bipolar disorder, either to reducesymptoms of mania or depression, or as mood stabilisers to prevent theemergence of mood episodes. Clinical and preclinical evidence alsosuggests that use-dependent sodium channel blockers may help to reducethe symptoms of schizophrenia. For example, lamotrigine has been shownto reduce symptoms of psychosis induced by ketamine in healthy humanvolunteers, and furthermore, studies in patients suggest that the drugcan augment the antipsychotic efficacy of some atypical antipsychoticdrugs, such as clozapine or olanzapine. It is hypothesised that efficacyin these psychiatric disorders may result in part from a reduction ofexcessive glutamate release. The reduction in glutamate release isthought to be a consequence of use-dependent sodium channel inhibitionin key brain areas, such as the frontal cortex. However, interactionwith voltage-gated calcium channels may also contribute to the efficacyof these drugs.

International published patent application WO05/000309 (IonixPharmaceuticals Limited) discloses the use of compounds of formula (I),wherein R₁ is an organic substituent, X₁ and X₂ are direct bonds orspacer moieties, Ar is aryl or heteroaryl and Y is a substitutedaminoalkyl group or a heteroaryl-, heterocyclyl- or phenyl-containingmoiety:

Such compounds are inhibitors of sensory neurone specific sodiumchannels and are said to be useful in the treatment of chronic and acutepain, tinnitus, bowel disorders, bladder dysfunction and demyelinatingdiseases.

International published patent application WO04/083189 (Merck & Co.)discloses biaryl substituted triazole compounds of formula (I), (II) and(III) as sodium channel blockers:

Such compounds are said to be useful in the treatment of conditionsassociated with sodium channel activity including, for example, acutepain, chronic pain, visceral pain, epilepsy, irritable bowel syndrome,depression and others.

International published patent application WO04/092140 (Merck & Co.)discloses biaryl substituted pyrazoles of formula (I), (II), (III) and(IV) as sodium channel blockers:

The compounds are said to be useful in the treatment of conditionsincluding acute pain, chronic pain, visceral pain, inflammatory pain andneuropathic pain.

International published patent application WO04/094395 (Merck & Co.)discloses birayl substituted thiazoles, oxazoles and imidazoles offormula (I) as sodium channel blockers:

The compounds are said to be useful in the treatment of conditionsincluding acute pain, chronic pain, visceral pain, inflammatory pain andneuropathic pain.

International patent application WO04/026826 (F. Hoffman La Roche AG)discloses 4-pyrrolidinophenyl-benzyl ether derivatives of formula (I):

The compounds are said to be monoamine oxidase B inhibitors and are saidto be useful in the treatment of conditions such as Alzheimer's diseaseor senile dementia.

The object of the present invention is to identify a compound whichmodulates voltage-gated sodium channels.

In one embodiment, the compound will be a use dependent sodium channelinhibitor.

In another embodiment, the compound will be a subtype NaV1.3 sodiumchannel use dependent inhibitor.

Another object of the invention is to identify a use dependent sodiumchannel inhibitor which has a suitable developability profile, forexample in terms of exposure (Cmax) and/or bioavailability on oraladministration.

According to a first aspect, the invention provides5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-prolinamide of formula (I),

or a pharmaceutically acceptable salt, a solvate or prodrug thereof.

Hereinafter, the compound of formula (I), its pharmaceuticallyacceptable salts, solvates and its prodrugs, defined in any aspect ofthe invention (except intermediate compounds in chemical processes) arereferred to as “the compounds of the invention”.

It will be appreciated by the person skilled in the art that thecompound of formula (I) may exist as four possible diastereoisomers. Ina further embodiment, the compound of the invention is selected from thelist consisting of:

-   (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide (Ia),

-   (5S)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-D-prolinamide (Ib),

-   (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-D-prolinamide (Ic)

and

-   (5S)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide (Id)

and pharmaceutically acceptable salts, solvates or prodrugs of (Ia),(Ib), (Ic) or (Id).

In a further embodiment the compound of the invention is(5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide (Ia), or apharmaceutically acceptable salt, solvate or prodrug thereof.

The diastereoisomers of the compound of formula (I) may be obtainedaccording to methods well known in the literature, for example bypreparative HPLC or by chromatographic purifications. A racemic mixturemay either be separated using preparative HPLC and a column with achiral stationary phase or resolved to yield individual enantiomersutilising methods known to those skilled in the art. In addition, chiralintermediate compounds may be resolved and used to prepare chiralcompounds of the invention.

The compound of formula (I) may form pharmaceutically or veterinarilyacceptable salts. The pharmaceutically or veterinarily acceptable saltsof the compound of formula (I) which contain a basic centre are, forexample, non-toxic acid addition salts formed with inorganic acids suchas hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid,with carboxylic acids or with organo-sulfonic acids. Examples includethe HCl, HBr, HI, sulfate or bisulfate, nitrate, phosphate or hydrogenphosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate,lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate salts.For reviews on suitable pharmaceutical salts see Berge et al, J. Pharm,Sci., 66, 1-19, 1977; P L Gould, International Journal of Pharmaceutics,33 (1986), 201-217; and Bighley et al, Encyclopedia of PharmaceuticalTechnology, Marcel Dekker Inc, New York 1996, Volume 13, page 453-497.

It will be appreciated by those skilled in the art that certainprotected derivatives of the compounds of formula (I), which may be madeprior to a final deprotection stage, may not possess pharmacologicalactivity as such, but may, in certain instances, be administered orallyor parenterally and thereafter metabolised in the body to form compoundsof the invention which are pharmacologically active. Such derivativesmay therefore be described as “prodrugs”. All such prodrugs of compoundsof the invention are included within the scope of the invention.Examples of pro-drug functionality suitable for the compounds of thepresent invention are described in Drugs of Today, Volume 19, Number 9,1983, pp 499-538 and in Topics in Chemistry, Chapter 31, pp 306-316 andin “Design of Prodrugs” by H. Bundgaard, Elsevier, 1985, Chapter 1 (thedisclosures in which documents are incorporated herein by reference). Itwill further be appreciated by those skilled in the art, that certainmoieties, known to those skilled in the art as “pro-moieties”, forexample as described by H. Bundgaard in “Design of Prodrugs” (thedisclosure in which document is incorporated herein by reference) may beplaced on appropriate functionalities when such functionalities arepresent within compounds of the invention.

Those skilled in the art of organic chemistry will appreciate that manyorganic compounds can form complexes with solvents in which they arereacted or from which they are precipitated or crystallized. Thesecomplexes are known as “solvates”. For example, a complex with water isknown as a “hydrate”. Pharmaceutically acceptable solvates of thecompound of the invention are within the scope of the invention.

The pharmaceutically acceptable solvates of the compounds of theinvention include hydrates thereof.

Also included within the scope of the compounds of the invention arepolymorphs thereof.

The compounds of the invention may exist in one or more tautomericforms. All tautomers and mixtures thereof are included in the scope ofthe present invention.

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine andchlorine such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and³⁶Cl, respectively. Certain isotopic variations of the invention, forexample, those in which a radioactive isotope such as ³H or ¹⁴C isincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with isotopes such as deuterium, i.e., ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements and hence may be preferred in some circumstances. Isotopicvariations of the compounds of the invention can generally be preparedby conventional procedures such as by the illustrative methods or by thepreparations described in the Examples hereafter using appropriateisotopic variations of suitable reagents.

According to a further aspect, the invention provides a process toprepare a compound of formula (I) comprising the reaction of a compoundof formula (II)

with a solution of ammonia in a suitable solvent.

In one embodiment, the solvent is methanol. In a further embodiment thesolution of ammonia in methanol is concentrated, for example a 7N or11.2 M solution.

In another embodiment the reaction is performed at room temperature.

As discussed hereinabove, it is believed that compounds of the inventionmay be useful for the treatment of diseases and conditions mediated bymodulation of voltage-gated sodium channels.

Therefore, according to a further aspect, the invention providescompounds of the invention for use as a medicament, preferably a humanmedicament.

According to a further aspect the invention provides the use ofcompounds of the invention in the manufacture of a medicament fortreating or preventing a disease or condition mediated by modulation ofvoltage-gated sodium channels.

Without wishing to be bound by theory, diseases or conditions that maybe mediated by modulation of voltage-gated sodium channels are selectedfrom the list consisting of [the numbers in brackets after the listeddiseases below refer to the classification code in Diagnostic andStatistical Manual of Mental Disorders, 4th Edition, published by theAmerican Psychiatric Association (DSM-IV) and/or the InternationalClassification of Diseases, 10th Edition (ICD-10)]:

i) Depression and mood disorders including Major Depressive Episode,Manic Episode, Mixed Episode and Hypomanic Episode; Depressive Disordersincluding Major Depressive Disorder, Dysthymic Disorder (300.4),Depressive Disorder Not Otherwise Specified (311); Bipolar Disordersincluding Bipolar I Disorder, Bipolar II Disorder (Recurrent MajorDepressive Episodes with Hypomanic Episodes) (296.89), CyclothymicDisorder (301.13) and Bipolar Disorder Not Otherwise Specified (296.80);Other Mood Disorders including Mood Disorder Due to a General MedicalCondition (293.83) which includes the subtypes With Depressive Features,With Major Depressive-like Episode, With Manic Features and With MixedFeatures), Substance-Induced Mood Disorder (including the subtypes WithDepressive Features, With Manic Features and With Mixed Features) andMood Disorder Not Otherwise Specified (296.90):ii) Schizophrenia including the subtypes Paranoid Type (295.30),Disorganised Type (295.10), Catatonic Type (295.20), UndifferentiatedType (295.90) and Residual Type (295.60); Schizophreniform Disorder(295.40); Schizoaffective Disorder (295.70) including the subtypesBipolar Type and Depressive Type; Delusional Disorder (297.1) includingthe subtypes Erotomanic Type, Grandiose Type, Jealous Type, PersecutoryType, Somatic Type, Mixed Type and Unspecified Type; Brief PsychoticDisorder (298.8); Shared Psychotic Disorder (297.3); Psychotic DisorderDue to a General Medical Condition including the subtypes With Delusionsand With Hallucinations; Substance-Induced Psychotic Disorder includingthe subtypes With Delusions (293.81) and With Hallucinations (293.82);and Psychotic Disorder Not Otherwise Specified (298.9).iii) Anxiety disorders including Panic Attack; Panic Disorder includingPanic Disorder without Agoraphobia (300.01) and Panic Disorder withAgoraphobia (300.21); Agoraphobia; Agoraphobia Without History of PanicDisorder (300.22), Specific Phobia (300.29, formerly Simple Phobia)including the subtypes Animal Type, Natural Environment Type,Blood-Injection-Injury Type, Situational Type and Other Type), SocialPhobia (Social Anxiety Disorder, 300.23), Obsessive-Compulsive Disorder(300.3), Posttraumatic Stress Disorder (309.81), Acute Stress Disorder(308.3), Generalized Anxiety Disorder (300.02), Anxiety Disorder Due toa General Medical Condition (293.84), Substance-Induced AnxietyDisorder, Separation Anxiety Disorder (309.21), Adjustment Disorderswith Anxiety (309.24) and Anxiety Disorder Not Otherwise Specified(300.00):iv) Substance-related disorders including Substance Use Disorders suchas Substance Dependence, Substance Craving and Substance Abuse;Substance-Induced Disorders such as Substance Intoxication, SubstanceWithdrawal, Substance-Induced Delirium, Substance-Induced PersistingDementia, Substance-Induced Persisting Amnestic Disorder,Substance-Induced Psychotic Disorder, Substance-Induced Mood Disorder,Substance-Induced Anxiety Disorder, Substance-Induced SexualDysfunction, Substance-Induced Sleep Disorder and HallucinogenPersisting Perception Disorder (Flashbacks); Alcohol-Related Disorderssuch as Alcohol Dependence (303.90), Alcohol Abuse (305.00), AlcoholIntoxication (303.00), Alcohol Withdrawal (291.81), Alcohol IntoxicationDelirium, Alcohol Withdrawal Delirium, Alcohol-Induced PersistingDementia, Alcohol-Induced Persisting Amnestic Disorder, Alcohol-InducedPsychotic Disorder, Alcohol-Induced Mood Disorder, Alcohol-InducedAnxiety Disorder, Alcohol-Induced Sexual Dysfunction, Alcohol-InducedSleep Disorder and Alcohol-Related Disorder Not Otherwise Specified(291.9); Amphetamine (or Amphetamine-Like)-Related Disorders such asAmphetamine Dependence (304.40), Amphetamine Abuse (305.70), AmphetamineIntoxication (292.89), Amphetamine Withdrawal (292.0), AmphetamineIntoxication Delirium, Amphetamine Induced Psychotic Disorder,Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced SleepDisorder and Amphetamine-Related Disorder Not Otherwise Specified(292.9); Caffeine Related Disorders such as Caffeine Intoxication(305.90), Caffeine-Induced Anxiety Disorder, Caffeine-Induced SleepDisorder and Caffeine-Related Disorder Not Otherwise Specified (292.9);Cannabis-Related Disorders such as Cannabis Dependence (304.30),Cannabis Abuse (305.20), Cannabis Intoxication (292.89), CannabisIntoxication Delirium, Cannabis-Induced Psychotic Disorder,Cannabis-Induced Anxiety Disorder and Cannabis-Related Disorder NotOtherwise Specified (292.9); Cocaine-Related Disorders such as CocaineDependence (304.20), Cocaine Abuse (305.60), Cocaine Intoxication(292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium,Cocaine-Induced Psychotic Disorder, Cocaine-Induced Mood Disorder,Cocaine-Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction,Cocaine-Induced Sleep Disorder and Cocaine-Related Disorder NotOtherwise Specified (292.9); Hallucinogen-Related Disorders such asHallucinogen Dependence (304.50), Hallucinogen Abuse (305.30),Hallucinogen Intoxication (292.89), Hallucinogen Persisting PerceptionDisorder (Flashbacks) (292.89), Hallucinogen Intoxication Delirium,Hallucinogen-Induced Psychotic Disorder, Hallucinogen-Induced MoodDisorder, Hallucinogen-Induced Anxiety Disorder and Hallucinogen-RelatedDisorder Not Otherwise Specified (292.9); Inhalant-Related Disorderssuch as Inhalant Dependence (304.60), Inhalant Abuse (305.90), InhalantIntoxication (292.89), Inhalant Intoxication Delirium, Inhalant-InducedPersisting Dementia, Inhalant-Induced Psychotic Disorder,Inhalant-Induced Mood Disorder, Inhalant-Induced Anxiety Disorder andInhalant-Related Disorder Not Otherwise Specified (292.9);Nicotine-Related Disorders such as Nicotine Dependence (305.1), NicotineWithdrawal (292.0) and Nicotine-Related Disorder Not Otherwise Specified(292.9); Opioid-Related Disorders such as Opioid Dependence (304.00),Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal(292.0), Opioid Intoxication Delirium, Opioid-Induced PsychoticDisorder, Opioid-Induced Mood Disorder, Opioid-Induced SexualDysfunction, Opioid-Induced Sleep Disorder and Opioid-Related DisorderNot Otherwise Specified (292.9); Phencyclidine (orPhencyclidine-Like)-Related Disorders such as Phencyclidine Dependence(304.60), Phencyclidine Abuse (305.90), Phencyclidine Intoxication(292.89), Phencyclidine Intoxication Delirium, Phencyclidine-InducedPsychotic Disorder, Phencyclidine-Induced Mood Disorder,Phencyclidine-Induced Anxiety Disorder and Phencyclidine-RelatedDisorder Not Otherwise Specified (292.9); Sedative-, Hypnotic-, orAnxiolytic-Related Disorders such as Sedative, Hypnotic, or AnxiolyticDependence (304.10), Sedative, Hypnotic, or Anxiolytic Abuse (305.40),Sedative, Hypnotic, or Anxiolytic Intoxication (292.89), Sedative,Hypnotic, or Anxiolytic Withdrawal (292.0), Sedative, Hypnotic, orAnxiolytic Intoxication Delirium, Sedative, Hypnotic, or AnxiolyticWithdrawal Delirium, Sedative-, Hypnotic-, or Anxiolytic-PersistingDementia, Sedative-, Hypnotic-, or Anxiolytic-Persisting AmnesticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced PsychoticDisorder, Sedative-, Hypnotic-, or Anxiolytic-Induced Mood Disorder,Sedative-, Hypnotic-, or Anxiolytic-Induced Anxiety Disorder Sedative-,Hypnotic-, or Anxiolytic-Induced Sexual Dysfunction, Sedative-,Hypnotic-, or Anxiolytic-Induced Sleep Disorder and Sedative-,Hypnotic-, or Anxiolytic-Related Disorder Not Otherwise Specified(292.9); Polysubstance-Related Disorder such as Polysubstance Dependence(304.80); and Other (or Unknown) Substance-Related Disorders such asAnabolic Steroids, Nitrate Inhalants and Nitrous Oxide:v) Enhancement of cognition including the treatment of cognitionimpairment in other diseases such as schizophrenia, bipolar disorder,depression, other psychiatric disorders and psychotic conditionsassociated with cognitive impairment, e.g. Alzheimer's disease:vi) Sleep disorders including primary sleep disorders such as Dyssomniassuch as Primary Insomnia (307.42), Primary Hypersomnia (307.44),Narcolepsy (347), Breathing-Related Sleep Disorders (780.59), CircadianRhythm Sleep Disorder (307.45) and Dyssomnia Not Otherwise Specified(307.47); primary sleep disorders such as Parasomnias such as NightmareDisorder (307.47), Sleep Terror Disorder (307.46), Sleepwalking Disorder(307.46) and Parasomnia Not Otherwise Specified (307.47); SleepDisorders Related to Another Mental Disorder such as Insomnia Related toAnother Mental Disorder (307.42) and Hypersomnia Related to AnotherMental Disorder (307.44); Sleep Disorder Due to a General MedicalCondition, in particular sleep disturbances associated with suchdiseases as neurological disorders, neuropathic pain, restless legsyndrome, heart and lung diseases; and Substance-Induced Sleep Disorderincluding the subtypes Insomnia Type, Hypersomnia Type, Parasomnia Typeand Mixed Type; sleep apnea and jet-lag syndrome:vii) Eating disorders such as Anorexia Nervosa (307.1) including thesubtypes Restricting Type and Binge-Eating/Purging Type; Bulimia Nervosa(307.51) including the subtypes Purging Type and Nonpurging Type;Obesity; Compulsive Eating Disorder; Binge Eating Disorder; and EatingDisorder Not Otherwise Specified (307.50):viii) Autism Spectrum Disorders including Autistic Disorder (299.00),Asperger's Disorder (299.80), Rett's Disorder (299.80), ChildhoodDisintegrative Disorder (299.10) and Pervasive Disorder Not OtherwiseSpecified (299.80, including Atypical Autism).ix) Attention-Deficit/Hyperactivity Disorder including the subtypesAttention-Deficit/Hyperactivity Disorder Combined Type (314.01),Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Type(314.00), Attention-Deficit/Hyperactivity Disorder Hyperactive-ImpulseType (314.01) and Attention-Deficit/Hyperactivity Disorder Not OtherwiseSpecified (314.9); Hyperkinetic Disorder; Disruptive Behaviour Disorderssuch as Conduct Disorder including the subtypes childhood-onset type(321.81), Adolescent-Onset Type (312.82) and Unspecified Onset (312.89),Oppositional Defiant Disorder (313.81) and Disruptive Behaviour DisorderNot Otherwise Specified; and Tic Disorders such as Tourette's Disorder(307.23):x) Personality Disorders including the subtypes Paranoid PersonalityDisorder (301.0), Schizoid Personality Disorder (301.20), SchizotypalPersonality Disorder (301.22), Antisocial Personality Disorder (301.7),Borderline Personality Disorder (301.83), Histrionic PersonalityDisorder (301.50), Narcissistic Personality Disorder (301.81), AvoidantPersonality Disorder (301.82), Dependent Personality Disorder (301.6),Obsessive-Compulsive Personality Disorder (301.4) and PersonalityDisorder Not Otherwise Specified (301.9): andxi) Sexual dysfunctions including Sexual Desire Disorders such asHypoactive Sexual Desire Disorder (302.71), and Sexual Aversion Disorder(302.79); sexual arousal disorders such as Female Sexual ArousalDisorder (302.72) and Male Erectile Disorder (302.72); orgasmicdisorders such as Female Orgasmic Disorder (302.73), Male OrgasmicDisorder (302.74) and Premature Ejaculation (302.75); sexual paindisorder such as Dyspareunia (302.76) and Vaginismus (306.51); SexualDysfunction Not Otherwise Specified (302.70); paraphilias such asExhibitionism (302.4), Fetishism (302.81), Frotteurism (302.89),Pedophilia (302.2), Sexual Masochism (302.83), Sexual Sadism (302.84),Transvestic Fetishism (302.3), Voyeurism (302.82) and Paraphilia NotOtherwise Specified (302.9); gender identity disorders such as GenderIdentity Disorder in Children (302.6) and Gender Identity Disorder inAdolescents or Adults (302.85); and Sexual Disorder Not OtherwiseSpecified (302.9).xii) Impulse control disorder” including: Intermittent ExplosiveDisorder (312.34), Kleptomania (312.32), Pathological Gambling (312.31),Pyromania (312.33), Trichotillomania (312.39), Impulse-Control DisordersNot Otherwise Specified (312.3), Binge Eating, Compulsive Buying,Compulsive Sexual Behaviour and Compulsive Hoarding.

In another embodiment, diseases or conditions that may be mediated bymodulation of voltage gated sodium channels are depression or mooddisorders.

In another embodiment, diseases or conditions that may be mediated bymodulation of voltage gated sodium channels are substance relateddisorders.

In a further embodiment, diseases or conditions that may be mediated bymodulation of voltage gated sodium channels are Bipolar Disorders(including Bipolar I Disorder, Bipolar II Disorder (i.e. Recurrent MajorDepressive Episodes with Hypomanic Episodes) (296.89), CyclothymicDisorder (301.13) or Bipolar Disorder Not Otherwise Specified (296.80)).

In a still further embodiment, diseases or conditions that may bemediated by modulation of voltage gated sodium channels areNicotine-Related Disorders such as Nicotine Dependence (305.1), NicotineWithdrawal (292.0) or Nicotine-Related Disorder Not Otherwise Specified(292.9).

In an embodiment, compounds of the invention may be useful asanalgesics. For example they may be useful in the treatment of chronicinflammatory pain (e.g. pain associated with rheumatoid arthritis,osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenilearthritis); musculoskeletal pain; lower back and neck pain; sprains andstrains; neuropathic pain; sympathetically maintained pain; myositis;pain associated with cancer and fibromyalgia; pain associated withmigraine; pain associated with influenza or other viral infections, suchas the common cold; rheumatic fever; pain associated with functionalbowel disorders such as non-ulcer dyspepsia, non-cardiac chest pain andirritable bowel syndrome; pain associated with myocardial ischemia; postoperative pain; headache; toothache; and dysmenorrhea.

Compounds of the invention may be useful in the treatment of neuropathicpain. Neuropathic pain syndromes can develop following neuronal injuryand the resulting pain may persist for months or years, even after theoriginal injury has healed. Neuronal injury may occur in the peripheralnerves, dorsal roots, spinal cord or certain regions in the brain.Neuropathic pain syndromes are traditionally classified according to thedisease or event that precipitated them. Neuropathic pain syndromesinclude: diabetic neuropathy; sciatica; non-specific lower back pain;multiple sclerosis pain; fibromyalgia; HIV-related neuropathy;post-herpetic neuralgia; trigeminal neuralgia; and pain resulting fromphysical trauma, amputation, cancer, toxins or chronic inflammatoryconditions. These conditions are difficult to treat and although severaldrugs are known to have limited efficacy, complete pain control israrely achieved. The symptoms of neuropathic pain are incrediblyheterogeneous and are often described as spontaneous shooting andlancinating pain, or ongoing, burning pain. In addition, there is painassociated with normally non-painful sensations such as “pins andneedles” (paraesthesias and dysesthesias), increased sensitivity totouch (hyperesthesia), painful sensation following innocuous stimulation(dynamic, static or thermal allodynia), increased sensitivity to noxiousstimuli (thermal, cold, mechanical hyperalgesia), continuing painsensation after removal of the stimulation (hyperpathia) or an absenceof or deficit in selective sensory pathways (hypoalgesia).

Compounds of the invention may also be useful in the amelioration ofinflammatory disorders, for example in the treatment of skin conditions(e.g. sunburn, burns, eczema, dermatitis, psoriasis); ophthalmicdiseases; lung disorders (e.g. asthma, bronchitis, emphysema, allergicrhinitis, non-allergic rhinitis, cough, respiratory distress syndrome,pigeon fancier's disease, farmer's lung, chronic obstructive pulmonarydisease, (COPD); gastrointestinal tract disorders (e.g. Crohn's disease,ulcerative colitis, coeliac disease, regional ileitis, irritable bowelsyndrome, inflammatory bowel disease, gastroesophageal reflux disease);other conditions with an inflammatory component such as migraine,multiple sclerosis, myocardial ischemia.

Compounds of the invention may also be useful in the treatment and/orprevention of disorders treatable and/or preventable withanti-convulsive agents, such as epilepsy including post-traumaticepilepsy, obsessive compulsive disorders (OCD), sleep disorders(including circadian rhythm disorders, insomnia & narcolepsy), tics(e.g. Giles de la Tourette's syndrome), ataxias, muscular rigidity(spasticity), and temporomandibular joint dysfunction.

Compounds of the invention may also be useful in the treatment ofbladder hyperrelexia following bladder inflammation.

Compounds of the invention may also be useful in the treatment ofneurodegenerative diseases and neurodegeneration such as dementia,particularly degenerative dementia (including senile dementia,Alzheimer's disease, Pick's disease, Huntington's chorea, Parkinson'sdisease and Creutzfeldt-Jakob disease, motor neuron disease); Thecompounds may also be useful for the treatment of amyotrophic lateralsclerosis (ALS) and neuroinflamation.

Compounds of the invention may also be useful in neuroprotection and inthe treatment of neurodegeneration following stroke, cardiac arrest,pulmonary bypass, traumatic brain injury, spinal cord injury or thelike.

Compounds of the invention may also be useful in the treatment oftinnitus, and as local anaesthetics.

The compounds of the invention may also be used in combination withother therapeutic agents. The invention thus provides, in a furtheraspect, a combination comprising a compound of the invention or apharmaceutically acceptable derivative thereof together with a furthertherapeutic agent.

When a compound of the invention or a pharmaceutically acceptablederivative thereof is used in combination with a second therapeuticagent active against the same disease state the dose of each compoundmay differ from that when the compound is used alone. Appropriate doseswill be readily appreciated by those skilled in the art. It will beappreciated that the amount of a compound of the invention required foruse in treatment will vary with the nature of the condition beingtreated and the age and the condition of the patient and will beultimately at the discretion of the attendant physician or veterinarian.The compounds of the present invention may be used in combination withother [antithrombotic drugs such as thrombin inhibitors, thromboxanereceptor antagonists, prostacyclin mimetics, phosphodiesteraseinhibitors, fibrinogen antagonists, thrombolytic drugs such as tissueplaminogen activator and streptokinase, non-steroidal anti-inflammatorydrugs such as aspirin, and the like].

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with apharmaceutically acceptable carrier or excipient comprise a furtheraspect of the invention. The individual components of such combinationsmay be administered either sequentially or simultaneously in separate orcombined pharmaceutical formulations by any convenient route.

When administration is sequential, either the compound of the inventionor the second therapeutic agent may be administered first. Whenadministration is simultaneous, the combination may be administeredeither in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the formulation. When formulated separately they maybe provided in any convenient formulation, conveniently in such manneras are known for such compounds in the art.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent psychotic disorders: i)antipsychotics; ii) drugs for extrapyramidal side effects, for exampleanticholinergics (such as benztropine, biperiden, procyclidine andtrihexyphenidyl), antihistamines (such as diphenhydramine) anddopaminergics (such as amantadine); iii) antidepressants; iv)anxiolytics; and v) cognitive enhancers for example cholinesteraseinhibitors (such as tacrine, donepezil, rivastigmine and galantamine).

The compounds of the invention may be used in combination withantidepressants to treat or prevent depression and mood disorders.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent bipolar disease: i) moodstabilisers; ii) antipsychotics; and iii) antidepressants.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent anxiety disorders: i) anxiolytics;and ii) antidepressants.

The compounds of the invention may be used in combination with thefollowing agents to improve nicotine withdrawal and reduce nicotinecraving: i) nicotine replacement therapy for example a sublingualformulation of nicotine beta-cyclodextrin and nicotine patches; and ii)bupropion.

The compounds of the invention may be used in combination with thefollowing agents to improve alcohol withdrawal and reduce alcoholcraving: i) NMDA receptor antagonists for example acamprosate; ii) GABAreceptor agonists for example tetrabamate; and iii) Opioid receptorantagonists for example naltrexone.

The compounds of the invention may be used in combination with thefollowing agents to improve opiate withdrawal and reduce opiate craving:i) opioid mu receptor agonist/opioid kappa receptor antagonist forexample buprenorphine; ii) opioid receptor antagonists for examplenaltrexone; and iii) vasodilatory antihypertensives for examplelofexidine.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent sleeping disorders: i)benzodiazepines for example temazepam, lormetazepam, estazolam andtriazolam; ii) non-benzodiazepine hypnotics for example zolpidem,zopiclone, zaleplon and indiplon; iii) barbiturates for exampleaprobarbital, butabarbital, pentobarbital, secobarbita andphenobarbital; iv) antidepressants; v) other sedative-hypnotics forexample chloral hydrate and chlormethiazole.

The compounds of the invention may be used in combination with thefollowing agents to treat anorexia: i) appetite stimulants for examplecyproheptidine; ii) antidepressants; iii) antipsychotics; iv) zinc; andv) premenstrual agents for example pyridoxine and progesterones.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent bulimia: i) antidepressants; ii)opioid receptor antagonists; iii) antiemetics for example ondansetron;iv) testosterone receptor antagonists for example flutamide; v) moodstabilisers; vi) zinc; and vii) premenstrual agents.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent autism: i) antipsychotics; ii)antidepressants; iii) anxiolytics; and iv) stimulants for examplemethylphenidate, amphetamine formulations and pemoline.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent ADHD: i) stimulants for examplemethylphenidate, amphetamine formulations and pemoline; and ii)non-stimulants for example norepinephrine reuptake inhibitors (such asatomoxetine), alpha 2 adrenoceptor agonists (such as clonidine),antidepressants, modafinil, and cholinesterase inhibitors (such asgalantamine and donezepil).

The compounds of the invention may be used in combination with thefollowing agents to treat personality disorders: i) antipsychotics; ii)antidepressants; iii) mood stabilisers; and iv) anxiolytics.

The compounds of the invention may be used in combination with thefollowing agents to treat or prevent male sexual dysfunction: i)phosphodiesterase V inhibitors, for example vardenafil and sildenafil;ii) dopamine agonists/dopamine transport inhibitors for exampleapomorphine and buproprion; iii) alpha adrenoceptor antagonists forexample phentolamine; iv) prostaglandin agonists for examplealprostadil; v) testosterone agonists such as testosterone; vi)serotonin transport inhibitors for example serotonin reuptakeinhibitors; v) noradrenaline transport inhibitors for example reboxetineand vii) 5-HT1A agonists, for example flibanserine.

The compounds of the invention may be used in combination with the sameagents specified for male sexual dysfunction to treat or prevent femalesexual dysfunction, and in addition an estrogen agonist such asestradiol.

Antipsychotic drugs include Typical Antipsychotics (for examplechlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine,prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindoneand loxapine); and Atypical Antipsychotics (for example clozapine,olanzapine, risperidone, quetiapine, aripirazole, ziprasidone andamisulpride).

Antidepressant drugs include serotonin reuptake inhibitors (such ascitalopram, escitalopram, fluoxetine, paroxetine and sertraline); dualserotonin/noradrenaline reuptake inhibitors (such as venlafaxine,duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such asreboxetine); tricyclic antidepressants (such as amitriptyline,clomipramine, imipramine, maprotiline, nortriptyline and trimipramine);monoamine oxidase inhibitors (such as isocarboxazide, moclobemide,phenelzine and tranylcypromine); and others (such as bupropion,mianserin, mirtazapine, nefazodone and trazodone).

Mood stabiliser drugs include lithium, sodium valproate/valproicacid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate andtiagabine.

Anxiolytics include benzodiazepines such as alprazolam and lorazepam.

It will be appreciated that references herein to “treatment” extend toprophylaxis, prevention of recurrence and suppression or amelioration ofsymptoms (whether mild, moderate or severe) as well as the treatment ofestablished conditions.

The compound of the invention may be administered as the raw chemicalbut the active ingredient is preferably presented as a pharmaceuticalformulation.

According to a further aspect, the invention provides a pharmaceuticalcomposition comprising a compound of the invention, in association withone or more pharmaceutically acceptable carrier(s), diluents(s) and/orexcipient(s). The carrier, diluent and/or excipient must be “acceptable”in the sense of being compatible with the other ingredients of thecomposition and not deleterious to the recipient thereof.

The compounds of the invention may be administered in conventionaldosage forms prepared by combining a compound of the invention withstandard pharmaceutical carriers or diluents according to conventionalprocedures well known in the art. These procedures may involve mixing,granulating and compressing or dissolving the ingredients as appropriateto the desired preparation.

The pharmaceutical compositions of the invention may be formulated foradministration by any route, and include those in a form adapted fororal, topical or parenteral administration to mammals including humans.

The compositions may be in the form of tablets, capsules, powders,granules, lozenges, creams or liquid preparations, such as oral orsterile parenteral solutions or suspensions.

The topical formulations of the present invention may be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present as from about 1% up to about 98% of theformulation. More usually they will form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatine, sorbitol,tragacanth, or polyvinylpyrrolidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavouring or colouring agents.

Suppositories will contain conventional suppository bases, e.g.cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are preparedutilising the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved in water for injection and filter-sterilisedbefore filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle. To enhance thestability, the composition can be frozen after filling into the vial andthe water removed under vacuum. The dry lyophilised powder is thensealed in the vial and an accompanying vial of water for injection maybe supplied to reconstitute the liquid prior to use. Parenteralsuspensions are prepared in substantially the same manner except thatthe compound is suspended in the vehicle instead of being dissolved andsterilisation cannot be accomplished by filtration. The compound can besterilised by exposure to ethylene oxide before suspending in thesterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound.

The compositions may contain from 0.1% by weight, for example from10-60% by weight, of the active material, depending on the method ofadministration. Where the compositions comprise dosage units, each unitwill for example contain from 5-1000 mg of the active ingredient. Thedosage as employed for adult human treatment may range from 10 to 3000mg per day depending on the route and frequency of administration. Fororal administration a typical dose may be in the range of 50 to 1500 mgper day, for example 120 to 800 mg per day.

It will be recognised by one of skill in the art that the optimalquantity and spacing of individual dosages of a compound of theinvention will be determined by the nature and extent of the conditionbeing treated, the form, route and site of administration, and theparticular mammal being treated, and that such optimums can bedetermined by conventional techniques. It will also be appreciated byone of skill in the art that the optimal course of treatment, i.e., thenumber of doses of a compound of the invention given per day for adefined number of days, can be ascertained by those skilled in the artusing conventional course of treatment determination tests.

All publications, including, but not limited to, patents and patentapplications cited in this specification, are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

It will be appreciated that the invention includes the following furtheraspects. The embodiments described for the first aspect similarly applyto these further aspects.

The diseases and conditions described above extend, where appropriate,to these further aspects.

-   -   i) A compound of the invention for use in treating or preventing        a disease or condition mediated by modulation of voltage-gated        sodium channels.    -   ii) A method of treatment or prevention of a disease or        condition mediated by modulation of voltage-gated sodium        channels in a mammal comprising administering an effective        amount of a compound of the invention.    -   iii) Use of a compound of the invention in the manufacture of a        medicament to treat or prevent a disease or condition mediated        by modulation of voltage-gated sodium channels.    -   iv) Use of a compound of the invention to treat or prevent a        disease or condition mediated by modulation of voltage-gated        sodium channels.

Experimentals

The invention is illustrated by the Examples described below.

In the procedures that follow, after each starting material, referenceto a Description or Example by number is typically provided. This isprovided merely for assistance to the skilled chemist. The startingmaterial may not necessarily have been prepared from the batch referredto.

Where reference is made to the use of a “similar” procedure, as will beappreciated by those skilled in the art, such a procedure may involveminor variation, for example reaction temperature, reagent/solventamount, reaction time, work-up conditions or chromatographicpurification conditions.

The compounds described in the Examples described hereinafter have allbeen prepared as a first step from stereochemically pure methyl5-oxo-L-prolinate or ethyl 5-oxo-D-prolinate, for example 99% ee. Thestereochemistry of the compounds of the Descriptions and Examples havebeen assigned on the assumption that the pure configuration of5-oxo-prolinate is maintained throughout any subsequent reactionconditions.

The absolute configuration of the stereocenter at the 2-position asshown below the has been assigned on the basis of NOE ¹H NMRexperiments, by determining the relative stereochemistry of thisstereocenter with respect to the one at the 5-position.

Compounds are named using ACD/Name PRO 6.02 chemical naming software(Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada).

Proton Magnetic Resonance (NMR) spectra are typically recorded either onVarian instruments at 300, 400, 500 or 600 MHz, or on a Brukerinstrument at 300 MHz and 400 MHz. Chemical shifts are reported in ppm(δ) using the residual solvent line as internal standard. Splittingpatterns are designed as s, singlet; d, doublet; t, triplet; q, quartet;m, multiplet; b, broad. The NMR spectra were recorded at a temperatureranging from 25 to 90° C. When more than one conformer was detected thechemical shifts for the most abundant one is reported.

HPLC analysis indicated by R_(t)(HPLC): x min, was performed on anAgilent 1100 series instrument using a Luna 3u C18(2) 100A (50×2.0 mm)column (mobile phase: 100% [water+0.05% TFA] to 95% [acetonitrile+0.05%TFA] in 8 min, flux=1 ml/min, detection wavelength 220 nm.

Mass spectra (MS) are typically taken on a 4 II triple quadrupole MassSpectrometer (Micromass UK) or on a Agilent MSD 1100 Mass Spectrometer,operating in ES (+) and ES (−) ionization mode or on a Agilent LC/MSD1100 Mass Spectrometer, operating in ES (+) and ES (−) ionization modecoupled with HPLC instrument Agilent 1100 Series [LC/MS—ES (+):analysisperformed on a Supelcosil ABZ+Plus (33×4.6 mm, 3 μm) (mobile phase: 100%[water+0.1% HCO₂H] for 1 min, then from 100% [water+0.1% HCO₂H] to 5%[water+0.1% HCO₂H] and 95% [CH₃CN] in 5 min, finally under theseconditions for 2 min; T=40° C.; flux=1 mL/min; LC/MS—ES (−):analysisperformed on a Supelcosil ABZ+Plus (33×4.6 mm, 3 μm) (mobile phase: 100%[water+0.05% NH₃] for 1 min, then from 100% [water+0.05% NH₃ to 5%[water+0.05% NH₃] and 95% [CH₃CN] in 5 min, finally under theseconditions for 2 min; T=40° C.; flux=1 mL/min]. In the mass spectra onlyone peak in the molecular ion cluster is reported.

The optical rotation was measured on a JASCO DIP-360 digital polarimeter(λ=589 nm, T=20° C., c=1 in MeOH).

Flash silica gel chromatography are typically carried out on silica gel230-400 mesh (supplied by Merck AG Darmstadt, Germany) or over VarianMega Be—Si pre-packed cartridges or over pre-packed Biotage silicacartridges.

SPE-SCX cartridges are ion exchange solid phase extraction columns bysupplied by Varian. The eluent used with SPE-SCX cartridges is methanolfollowed by 2N ammonia solution in methanol.

In a number of preparation purification was performed using eitherBiotage manual flash chromatography (Flash+) or automatic flashchromatography (Horizon) systems. All these instruments work withBiotage Silica cartridge.

SPE-Si cartridges are silica solid phase extraction columns supplied byVarian.

It will be recognised that spectra and diffraction data will varyslightly according to various factors such as the temperature,concentration and instrumentation used. The skilled person willrecognise that XRPD peak positions are affected by differences in sampleheight. The peak positions quoted herein are thus subject to a variationof +/−0.15 degrees 2-theta.

X-Ray Powder Diffraction

X Ray Powder Diffraction (XRPD) analysis was performed on Bruker D5005,using Sol-X detector. The acquisition conditions were: radiation: Cu Kα,generator tension: 40 kV, generator current: 50 mA, start angle: 2.0°2θ, end angle: 45.0 °2θ, step size: 0.02 °2θ, time per step: 1 seconds.The sample was prepared on zero background sample holder.

Differential Scanning Calorimetry (DSC): It should be recognized thatthe endotherm peak as measured is dependent under a number of factorsincluding the machine employed, the rate of heating, the calibrationstandard, humidity and the purity of the sample used.

Melting points reported in the experimentals are estimated on the basisof the onset of endotherm peaks registered during DSC analysis.

The following table lists the abbreviations used:

-   BOC2O bis(1,1-dimethylethyl) dicarbonate-   DCM—dichloromethane-   DIPEA—diisopropylethylamine-   DMAP—4-(dimethylamino)pyridine-   DMF—dimethylformamide    O-(benzotriazol-1-yl)-N,N,N′N'-tetramethyluronium-   TBTU—tetrafluoroborate-   THF—tetrahydrofuran-   TFA trifluoroacetic acid-   MTBE methyl-t-butyl ether-   Et2O Diethyl ether-   AcOEt Ethyl acetate-   MeOH Methyl alcohol-   DMSO Dimethyl sulfoxide

Description 1: 1-(1,1-dimethylethyl) 2-methyl(2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D1)

To a solution of commercially available methyl 5-oxo-L-prolinate (20 g,140 mmol) in DCM (200 ml) were added triethylamine (19.6 ml, 140 mmol),DMAP (17.2 g, 140 mmol) and then dropwise a solution of BOC₂O (61 g, 280mmol) in DCM (100 ml). The resulting red mixture was stirred at roomtemperature for 2 hours. Then the solvent was removed under reducedpressure and the crude material was purified by chromatography on silicagel eluting with cyclohexane/ethyl acetate (7:3 to 4:6) to afford (aftera trituration in hexane/diethylether 1:1) the title compound as a whitesolid (32.4 g, 96%); R_(f) (cyclohexanes:ethyl acetate=65:35): 0.21; ¹HNMR (300 MHz, CDCl₃) δ (ppm): 4.62 (dd, 1H), 3.78 (s, 3H), 2.68-2.58 (m,1H), 2.52-2.45 (m, 1H), 2.37-2.27 (m, 1H), 2.08-1.97 (m, 1H), 1.48 (s,9H).

Description 2: methyl(2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-oxo-5-{4-[(phenylmethyl)oxy]phenyl}pentanoate(D2)

n-Butyl lithium 1.6M solution in hexanes (0.88 ml, 1.4 mmol) was addeddropwise to a solution of commercially available1-bromo-4-[(phenylmethyl)oxy]benzene (390 mg, 1.48 mmol) in dry THF (2ml) at −78° C. under nitrogen atmosphere. The resulting suspension wasstirred at −78° C. for 40 minutes and then it was added dropwise to asolution of 1-(1,1-dimethylethyl) 2-methyl(2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D1, 300 mg, 1.23 mmol) in dryTHF (2.4 ml) previously cooled to −78° C. The mixture was stirred at−78° C. for 40 minutes and at −40° C. for 1 h, then it was quenched at−40° C. with an aqueous saturated ammonium chloride solution. Themixture was diluted with water and extracted with ethyl acetate. Theorganic phase was then washed with brine, dried over Na₂SO₄, andevaporated under reduced pressure to give the crude material, which waspurified by chromatography on silica gel eluting withcyclohexane/ethylacetate (95:5), thus affording the title compound as awhite solid (170 mg, 32%); R_(f) (cyclohexane:ethyl acetate=8:2): 0.30;¹HNMR (300 MHz, CDCl₃) δ (ppm): 7.95 (d, 2H), 7.50-7.33 (m, 5H), 7.03(d, 2H), 5.20 (bs, 1H), 5.15 (s, 2H), 4.45-4.35 (m, 1H), 3.78 (s, 3H),3.15-2.95 (m, 2H), 2.36-2.26 (m, 1H), 2.16-2.02 (m, 1H), 1.45 (s, 9H).

Description 3: methyl(2S)-5-{4-[(phenylmethyl)oxy]phenyl}-3,4-dihydro-2H-pyrrole-2-carboxylate(D3)

To a solution of methyl(2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-oxo-5-{4-[(phenylmethyl)oxy]phenyl}pentanoate(D2, 323 mg, 0.75 mmol) in dry DCM (4 ml) at 0° C., under nitrogenatmosphere was added trifluoroacetic acid (1 ml) dropwise. The resultingpale pink solution was allowed to warm to room temperature over 1 hour,then it was evaporated under reduced pressure, affording the titlecompound (D7, 291 mg, 0.68 mmol, 91%) as a greenish oil which may beused in the next step without any further purification; R_(t) (HPLC):3.69 min; MS: (ES/+) m/z: 310 [MH⁺], C19H19NO3 requires 309.

Description 4: methyl (5R)-5-{4-[(phenylmethyl)oxy]phenyl}-L-prolinate(D4) Description 5: methyl(5S)-5-{4-[(phenylmethyl)oxy]phenyl}-L-prolinate (D5)

To a solution of methyl(2S)-5-{4-[(phenylmethyl)oxy]phenyl}-3,4-dihydro-2H-pyrrole-2-carboxylate(D3, 13.7 g, 32.4 mmol) in MeOH (200 ml) was added PtO₂ (240 mg) and themixture was stirred under a hydrogen atmosphere (2 atmos) for 6 hours.Then the catalyst was filtered off and the solvent removed under reducedpressure to give a red oil which was dissolved in ethyl acetate andwashed with NaHCO₃ solution.

The resulting crude material was purified by chromatography on silicagel eluting with cyclohexane/ethyl acetate (9:1 to 8:2) to afford thetitle compounds:

D4, 4.15 g, 13.3 mmol, Y=41%. MS: (ES/+) m/z: 312 [MH⁺]. C19H21NO3requires 311. Rt (HPLC): 3.80 min. Rf (cyclohexane:ethyl acetate=7:3):0.18. ¹HNMR (300 MHz, CDCl₃) δ (ppm): 7.40 (d, 2H); 7.35 (t, 2H); 7.33(d, 2H); 7.29 (t, 1H); 6.93 (d, 2H); 5.03 (s, 2H); 4.23 (dd, 1H); 4.00(dd, 1H); 3.71-3.79 (m, 3H); 2.18-2.30 (m, 1H); 2.09-2.18 (m, 2H);1.67-1.78 (m, 1H). NOE between the proton at C2 and the proton at C5could be observed.

D5, 0.6 g, 1.9 mmol, Y=6%. MS: (ES/+) m/z: 312 [MH⁺]. C19H21NO3 requires311; Rt (HPLC): 3.73 min. Rf (cyclohexane:ethyl acetate=7:3): 0.32.¹HNMR (300 MHz, CDCl₃) δ (ppm): 7.40 (d, 2H); 7.35 (t, 2H); 7.29 (d,2H); 7.28 (t, 1H); 6.91 (d, 2H); 4.97-5.07 (m, 2H); 4.29 (dd, 1H); 4.09(dd, 1H); 3.71-3.75 (m, 3H); 2.29-2.42 (m, 1H); 2.09-2.20 (m, 1H);1.90-2.02 (m, 1H); 1.69-1.82 (m, 1H). NOE between the proton at C2 andthe proton at C5 was not observed.

Description 6: (5R)-5-{4-[(phenylmethyl)oxy]phenyl}-L-proline (D6)Description 7:(5R)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-5-{4-[(phenylmethyl)oxy]phenyl}-L-proline(D7)

To a solution of methyl (5R)-5-{4-[(phenylmethyl)oxy]phenyl}-L-prolinate(D4, 120 mg, 0.38 mmol) in THF (2.3 ml) was added LiOH monohydrate (26mg, 0.61 mmol) dissolved in water (1.1 ml), followed by methanol (1.1ml). The resulting solution was stirred at room temperature for 2.5hours, then left overnight at −18° C. Then the organic solvent wasevaporated under reduced pressure maintaining the temperature at 38° C.and the aqueous residue containing the acid intermediate (D6, Rt(HPLC)=3.63 min. MS: (ES/+) m/z: 298 [MH⁺]. C18H19NO3 requires 297) wastreated with BOC₂O (168 mg, 0.77 mmol) dissolved in THF (1.1 ml). Thereaction mixture was stirred at room temperature for 3.5 hours. Theorganic solvent was evaporated and the basic aqueous solution wasacidified at 0° C. with aqueous 1N HCl solution to pH=3, this acidicaqueous solution was extracted with ethyl acetate (2×10 ml). The organicphase dried over Na₂SO₄ and evaporated under reduced pressure gave asolid, which was titurated in n-hexanes (3×6 ml) affording the titlecompound as a white powder (D7, 137 mg, 90% for two steps); Rt (HPLC):5.81 min; Rf (cyclohexane:ethyl acetate=1:1): 0.34; MS: (ES/+) m/z: 420[M+Na⁺] C23H27NO5 requires 397; MS: (ES/−) m/z: 396 [M−H] C23H27NO5requires 397; ¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.5-7.3 (m, 5H), 7.10(bm, 2H), 6.90 (d, 2H), 5.08 (s, 2H), 4.65 (bm, 1H), 4.50 (bm, 1H), 2.58(bm, 1H), 2.31 (bm, 1H), 2.11-1.90 (m, 2H), 1.16 (s, 9H).

Description 8: 1,1-dimethylethyl(2S,5R)-2-(aminocarbonyl)-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate(D8)

To a solution of(5R)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-5-{4-[(phenylmethyl)oxy]phenyl}-L-proline(D7, 1.44 g, 3.62 mmol) in dry DMF (20 ml) were added DIPEA (1.26 ml,7.24 mmol), then TBTU (1.23 g, 3.98 mmol) and after 20 minutes,1,1,1,3,3,3-hexamethyldisilazane (1.15 ml, 5.43 mmol). The reactionmixture was stirred at room temperature for 2 h, then it was treatedwith aqueous 5% NaHCO₃ solution (30 ml) and stirred for further 30minutes. The resulting mixture was diluted with water and extracted withethyl acetate. The organic phase was then washed twice with brine/ice,dried over Na₂SO₄ and evaporated to give a colourless oil. This crudematerial was purified by chromatography on silica gel eluting withcyclohexane/ethyl acetate (7:3 to 5:5) to afford the title compound(1.25 g, 87%); R_(t) (HPLC): 5.51 min; R_(f) (cyclohexane:ethylacetate=1:1): 0.29. MS: (ES/+) m/z: 419 [M+Na⁺]; C23H28N2O4 requires396.

Description 9: 1,1-dimethylethyl(2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidinecarboxylate(D9)

To a solution of 1,1-dimethylethyl(2S,5R)-2-(aminocarbonyl)-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate(D8, 1.2 g, 3.02 mmol) in methanol (25 ml) was added Pd/C 10% wt (210mg) and the mixture was stirred under hydrogen (1 atm) for 6 hours. Thecatalyst was filtered off and the solvent removed under reduced pressureto give the title compound as a white solid (870 mg, 94%); R_(t) (HPLC):3.61 min; R_(f) (cyclohexane:ethyl acetate=1:1): 0.18; MS: (ES/+) m/z:329 [M+Na⁺]. C16H22N2O4 requires 306; ¹H NMR (300 MHz, d₆-DMSO) δ ppm:9.15 (bs, 1H); 7.40 (bm, 2H); 7.30 (s, 1H); 6.90 (s, 1H); 6.65 (d, 2H);4.50-4.80 (m, 1H); 4.05-4.28 (m, 1H); 2.07-2.24 (m, 1H); 1.95-2.07 (m,1H); 1.60-1.89 (m, 2H); 1.00-1.45 (m, 9H).

Description 10: 1,1-dimethylethyl(2S,5R)-2-(aminocarbonyl)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1-pyrrolidinecarboxylate(D10)

1-(Bromomethyl)-2-fluorobenzene (30 μl, 0.220 mmol) was added to asolution of 1,1-dimethylethyl(2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidinecarboxylate(D9, 45 mg, 0.146 mmol) and potassium carbonate (30 mg, 0.217 mmol) inacetonitrile (2 ml). The mixture was stirred overnight at roomtemperature. After the reaction was finished, as shown by TLC, ethylacetate and water were added. The organic phase was then washed withbrine, dried (Na₂SO₄), filtered and evaporated. The crude material waspurified by chromatography on silica gel using cyclohexane/ethyl acetate(7:3 to 6:4) to afford the title compound (51 mg, 85%); Rt (HPLC): 5.56min; Rf (cyclohexane:ethyl acetate=1:1): 0.28; ¹H NMR (300 MHz, CDCl₃) δ(ppm): 7.56-7.48 (m, 1H); 7.37-7.28 (m, 1H); 7.24-7.06 (m, 5H); 6.93 (d,2H); 5.45-5.37 (br. s, 1H); 5.15 (s, 2H); 4.73-4.60 (m, 1H); 4.53-4.45(m, 1H); 2.58-2.48 (m, 1H); 2.34-2.25 (m, 1H); 2.09-1.93 (m, 2H);1.28-1.13 (br. s, 9H).

Description 11: (5S)-5-{4-[(phenylmethyl)oxy]phenyl}-L-proline (D11)

The title compound was synthesized following a similar procedure as setout earlier in Description 6 starting from methyl(5S)-5-{4-[(phenylmethyl)oxy]phenyl}-L-prolinate (D5, 600 mg, 1.92mmol); Rt (HPLC): 3.66 min; MS: (ES/−) m/z: 296 [M−H]; MS: (ES/+) m/z:298 [M+H], C18H19NO3 requires 297.

Description 12:(5S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-5-{4-[(phenylmethyl)oxy]phenyl}-L-proline(D12)

The title compound was synthesized (695 mg, 90% over two steps) asimilar procedure as set out earlier in Description 7 starting from((5S)-5-{4-[(phenylmethyl)oxy]phenyl}-L-proline (D11). The crudematerial may be used without any further purification in the next step;R(HPLC): 5.72 min; MS: (ES/−) m/z: 396 [M−H]; MS: (ES/+) m/z: 420[M+Na⁺], C23H27NO5 requires 397, ¹H NMR (400 MHz, DMSO-d6) δ (ppm):12.70-12.42 (br. s, 1H); 7.47-7.42 (m, 2H); 7.42-7.35 (m, 2H); 7.35-7.29(m, 1H); 7.13-7.07 (m, 2H); 6.98-6.92 (m, 2H); 5.08 and 5.06 (s,s, 2H);4.96-4.91 and 4.86-4.81 (m, m, 1H); 4.44-4.40 and 4.39-4.34 (m, m, 1H);2.36-2.13 (m, 2H); 1.90-1.80 (m, 1H); 1.69-1.57 (m, 1H); 1.33 and 1.09(s,s, 9H).

Description 13: 1,1-dimethylethyl(2S,5S)-2-(aminocarbonyl)-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate(D13)

The title compound was synthesized (600 mg, 87%) following a similarprocedure as set out earlier in Description 8 starting from(5S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-5-{4-[(phenylmethyl)oxy]phenyl}-L-proline(D12, 690 mg, crude material); R(HPLC): 5.23 min; MS: (ES/+) m/z: 419[M+Na⁺], C23H28N2O4 requires 396.

Description 14: 1,1-dimethylethyl(2S,5S)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidinecarboxylate(D14)

The title compound was synthesized (400 mg, 94%) following a similarprocedure as set out earlier in Description 9 starting from1,1-dimethylethyl(2S,5S)-2-(aminocarbonyl)-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate(D13, 550 mg, 1.38 mmol); Rt (HPLC): 3.14 min; MS: (ES/+) m/z: 329[M+Na⁺], C16H22N2O4 requires 306; ¹H NMR (400 MHz, DMSO-d6) δ (ppm):9.21 (br. s, 1H); 7.40-7.30 (br. s, 1H); 6.96-6.90 (m, 2H); 6.90-6.84(br. s, 1H); 6.71-6.64 (m, 2H); 4.90 and 4.80 (d, d, 1H); 4.32 and 4.25(d, d, 1H); 2.37-2.02 (m, 2H); 1.78-1.70 (m, 1H); 1.61-1.46 (m, 1H);1.32 and 1.09 (s,s, 9H).

Description 15: 1,1-dimethylethyl(2S,5S)-2-(aminocarbonyl)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1-pyrrolidinecarboxylate(D15)

1-(Bromomethyl)-2-fluorobenzene (30 μl, 0.244 mmol) was added to asolution of 1,1-dimethylethyl(2S,5S)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidinecarboxylate(D14, 50 mg, 0.163 mmol) and potassium carbonate (34 mg, 0.244 mmol) inacetonitrile (0.5 ml). The mixture was stirred overnight at roomtemperature. Then ethyl acetate (20 mL) and water (10 mL) were added.The organic phase was dried over Na₂SO₄, filtered and evaporated underreduced pressure. The crude material was purified by chromatography onsilica gel using cyclohexane/ethyl acetate (7:3 to 6:4) to afford thetitle compound (65 mg, 97%); R_(f) (cyclohexane:ethyl acetate=7:3):0.19; MS: (ES/+) m/z: 437 [M+Na⁺], C23H27FN2O4 requires 414; R_(t)(HPLC): 5.28 min; ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.54-7.44 (m, 1H),7.40-7.27 (m, 2H), 7.24-7.11 (m, 2H), 7.06-6.98 (m, 2H), 6.96-6.79 (m,3H), 5.10-5.00 (m, 2H), 4.91 and 4.81 (d, d, 1H), 4.29 and 4.24 (d, d,1H), 2.35-2.18 (m, 1H), 2.17-1.97 (m, 1H), 1.78-1.62 (m, 1H), 1.58-1.43(m, 1H), 1.28 and 1.03 (s, s, 9H).

Description 16: 1-(1,1-dimethylethyl) 2-ethyl(2R)-5-oxo-1,2-pyrrolidinedicarboxylate (D16)

The title compound was synthesized (14 g, 71%) following a similarprocedure as set out earlier in Description 1 starting from commerciallyavailable ethyl 5-oxo-D-prolinate (12 g, 75.6 mmol); R(cyclohexane:ethyl acetate=7:3): 0.25; R_(t) (HPLC) 3.94 min; ¹H NMR(400 MHz, DMSO-d6) δ (ppm): 4.61 (dd, 1H); 4.25 (q, 2H); 2.58-2.69 (m,1H); 2.44-2.55 (m, 1H); 2.26-2.38 (m, 1H); 2.00-2.08 (m, 1H); 1.50 (s,9H); 1.31 (t, 3H).

Description 17: Ethyl(2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-oxo-5-{4-[(phenylmethyl)oxy]phenyl}pentanoate(D17)

The title compound was synthesized (2.9 g, 16%) following a similarprocedure as set out earlier in Description 2 starting from1-(1,1-dimethylethyl) 2-ethyl (2R)-5-oxo-1,2-pyrrolidinedicarboxylate(D16, 10.5 g 40.8 mmol) and 4-iodophenyl phenylmethyl ether (13.34 g, 43mmol); Rt (HPLC): 6.37 min; MS: (ES/+) 464 m/z: [M+Na⁺], C25H31NO6requires 441; ¹H NMR (400 MHz, DMSO-d6) δ (ppm): 7.92 (d, 2H); 7.29-7.45(m, 5H); 6.99 (d, 2H); 5.18 (bs, 1H); 5.12 (s, 2H); 4.29-4.4 (bm, 1H);4.20 (q, 2H); 2.94-3.16 (m, 2H); 2.22-2.33 (m, 1H); 2.00-2.15 (m, 1H);1.39 (s, 9H); 1.28 (t, 3H).

Description 18: Ethyl(2R)-5-{4-[(phenylmethyl)oxy]phenyl}-3,4-dihydro-2H-pyrrole-2-carboxylate(D18)

The title compound was synthesized following a similar procedure as setout earlier in Description 3 starting from ethyl(2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-oxo-5-{4-[(phenylmethyl)oxy]phenyl}pentanoate(D17, 2.9 g, 6.57 mmol). The crude material may be used without anyfurther purification in the next step; R_(t) (HPLC): 3.80 min; MS:(ES/+) 324 m/z: C20H21NO3 requires 323.

Description 19: Ethyl (5S)-5-{4-[(phenylmethyl)oxy]phenyl}-D-prolinate(D19)

The title compound was synthesized (1.84 g, 86% over two steps)following a similar procedure as set out earlier in Description 4 usingthe crude material obtained from Description 18; Rt (HPLC): 4.03 min;MS: (ES/+) 326 m/z: [MH⁺], C20H23NO3 requires 325; ¹H NMR (500 MHz,CHCl3-d) δ (ppm): 7.30-7.47 (m, 7H), 6.96 (d, 2H), 5.06 (s, 2H), 4.23(q, 2H), 4.15 (dd, 1H), 3.90 (dd, 1H), 2.17-2.28 (m, 1H), 2.07-2.17 (m,2H), 1.61-1.76 (m, 1H), 1.31 (t, 3H).

Description 20: (5S)-5-{4-[(phenylmethyl)oxy]phenyl}-D-proline (D20)

The title compound was synthesized following a similar procedure as setout earlier in Description 6 starting from ethyl(5S)-5-{4-[(phenylmethyl)oxy]phenyl}-D-prolinate (D19, 340 mg, 1.045mmol); R^(t) (HPLC): 3.62 min; MS: (ES/+) 298 m/z: [MH⁺], C18H19NO3requires 297.

Description 21:(5S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-5-{4-[(phenylmethyl)oxy]phenyl}-D-proline(D21)

The title compound was synthesized (440 mg, quant. over two steps)following a similar procedure as set out earlier in Description 7starting from (5S)-5-{4-[(phenylmethyl)oxy]phenyl}-D-proline (D20); Rt(HPLC): 5.77 min; MS: (ES/+) 420 m/z: [M+Na⁺], C23H27NO5 requires 397;¹H-NMR (500 MHz, DMSO-d₆) δ (ppm): 12.55 (br.s., 1H); 6.65-6.78 (m, 7H);6.95 (d, 2H); 5.10 (s, 2H); 4.60-4.84 (m, 1H); 4.23 (m, 1H); 2.10-2.30(m, 2H); 1.63-1.95 (m, 2H); 1.05-1.39 (m, 9H).

Description 22: 1,1-dimethylethyl(2R,5S)-2-(aminocarbonyl)-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate(D22)

The title compound was synthesized (250 mg, 56%) following a similarprocedure as set out earlier in Description 8 starting from(5S)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-5-{4-[(phenylmethyl)oxy]phenyl}-D-proline(D21, 440 mg, 1.11 mmol); Rt (HPLC): 5.52 min; MS: (ES/+) 419 m/z:[M+Na⁺], C23H28N2O4 requires 396.

Description 23: 1,1-dimethylethyl(2R,5S)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidinecarboxylate(D23)

The title compound was synthesized (135 mg, quant.) following a similarprocedure as set out earlier in Description 9 starting from1,1-dimethylethyl(2R,5S)-2-(aminocarbonyl)-5-{4-[(phenylmethyl)oxy]phenyl}-1-pyrrolidinecarboxylate(D22, 175 mg, 0.44 mmol); Rt (HPLC): 3.63 min; MS: (ES/+) m/z: 329[M+Na⁺]. C16H22N2O4 requires 306; ¹H NMR (300 MHz, d₆-DMSO) δ (ppm):9.15 (bs, 1H); 7.40 (bm, 2H); 7.30 (s, 1H); 6.90 (s, 1H); 6.65 (d, 2H);4.50-4.80 (m, 1H); 4.05-4.28 (m, 1H); 2.07-2.24 (m, 1H); 1.95-2.07 (m,1H); 1.60-1.89 (m, 2H); 1.00-1.45 (m, 9H).

Description 24: 1,1-dimethylethyl(2R,5S)-2-(aminocarbonyl)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1-pyrrolidinecarboxylate(D24)

The title compound was synthesized (145 mg, 79%) following a similarprocedure as set out earlier in Description 10 starting from1,1-dimethylethyl(2R,5S)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-1-pyrrolidine carboxylate(D23, 130 mg, 0.44 mmol) and 1-(bromomethyl)-2-fluorobenzene (166 mg,0.88 mmol); Rt (HPLC) 5.55; MS: (ES/+) 437 m/z: [M+Na⁺], C23H27FN2O4requires 414; ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 7.48-7.63 (m, 3H);4.30-4.45 (m, 2H); 4.18-4.29 (m, 2H); 6.90-7.06 (m, 3H); 5.10 (s, 2H);4.56-4.82 (m, 1H); 4.10-4.18 (m, 1H); 2.12-2.26 (m, 1H); 1.98-2.12 (m,1H); 1.60-1.95 (m, 2H); 0.98-1.42 (m, 9H).

Description 25: 1-[(4-bromophenoxy)methyl]-2-fluorobenzene (D25)

Procedure 1: To a solution of 4-bromophenol (502.08 g) dissolved inacetone (7322 mL) was added K₂CO₃ (570 g) and then benzylbromide (523g). The mixture was heated under reflux for 2 hrs. The reaction mixturewas then cooled at 25° C., filtered and the filter cake was washed withMTBE (1046 mL). The combined filtrate was concentrated to 1000 mL andMTBE (4184 mL) were added. The mixture was washed with an aqueous 1MNaOH solution (1464 mL), then with brine (1300 mL) and the organic phasewas concentrated to dryness. THF (1300 mL) was added and the solvent wasremoved under reduced pressure to afford the title compound (902.1 g);¹H NMR (400 MHz, DMSO-d6) δ (ppm): 7.54 (td, 1H); 7.46 (d, 2H); 7.42 (m,1H); 7.23 (m, 2H); 7.01 (d, 2H); 5.13 (s, 2H).

D25 was also obtained as follows:

Procedure 2: A stirred mixture of 4-bromophenol (19.22 g, 111 mmol),orthofluorobenzyl bromide (20 g, 105.8 mmol) and potassium carbonate(21.9 g, 158.4 mmol) in acetone (280 ml) was heated at reflux for 6hours. The reaction mixture was cooled to room temperature and filtered,washing the solid with TBME (40 ml). The combined filtrate and washingswere concentrated under vacuum to a final volume of about 40 ml. Theresulting solution was diluted with TBME (160 ml) and washed with 1Msodium hydroxide and brine, then concentrated under vacuum to an oilwhich slowly solidified to give the title compound (28.9 g).

¹H NMR (300 MHz, CHCl3-d). δ (ppm): 5.10 (s, 2H), 6.86 (m, 2H), 7.10 (m,1H), 7.17 (m, 1H), 7.29 (m, 1H), 7.35 (m, 2H), 7.38 (m, 1H).

Description 26: methyl(2S)-2-{[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-5-oxopentanoate(D26)

Procedure 1: To a stirred suspension of magnesium metal (90 g) in dryTHF (600 mL) under a nitrogen atmosphere at room temperature was addediodine (0.3 g). The mixture was heated to an internal temperature of64+−2° C. A solution of 1-[(4-bromophenoxy)methyl]-2-fluorobenzene (D25)(693 g) in THF (1500 mL) was added in two batches. Firstly 45 mL wasadded. Secondly, the remaining solution (1455 mL) was added dropwise.After addition, the reaction was heated at reflux for 1 h. The reactionmixture was cooled to room temperature. This reaction mixture was thenadded slowly to a solution of commercially available 1-tert-butyl2-methyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (300 g) in THF (1500mL) cooled to −60° C., maintaining the internal temperature below −60°C. The addition was completed in 2 hours. The reaction mixture wasstirred for a further 15 minutes after addition. Isopropyl alcohol (300mL) was then added dropwise whilst maintaining the temperature below−60° C. A mixture of aqueous saturated ammonium chloridesolution/aqueous saturated sodium chloride solution (2/1; 900 mL) wasadded whilst maintaining the temperature at −50° C. Water (600 mL) wasadded to dissolve the yellow precipitate. The organic phase wasseparated and was washed with aqueous 13% NaCl solution (600 mL). Theorganic phase was concentrated to dryness. EtOAc (1500 mL) was thenadded and the solution was evaporated under reduced pressure to removewater. The residue was purified by chromatography on silica gel elutingwith cyclohexane/ethyl acetate (90:10 to 8:2) to afford the titlecompound (287 g); ¹H NMR (600 MHz, DMSO-d6) δ (ppm): 7.93 (d, 2H); 7.57(td, 1H); 7.44 (m, 1H); 7.27 (m, 3H); 7.14 (d, 2H); 5.24 (s, 2H); 4.04(m, 1H); 3.61 (s, 3H); 3.03 (m, 2H); 1.94 (m, 2H); 1.38 (s, 9H).

D26 was also obtained as follows:

Procedure 2: To a mixture of magnesium turnings (12.79 g. 533 mol), atrace of iodine and 1,2-dibromoethane in THF (86. ml) at 70-75° C., asolution of (4-bromophenyl (2-fluorophenyl)methyl ether) (D25, 100 g,355.6 mmol) in THF (216.25 ml) was added over about 2 hours. The mixturewas heated for a further 2 hours at 70-75° C. then cooled to roomtemperature to give a solution of the Grignard reagent. A solution of1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate(43.25 g, 177.8 mmol) in THF (216.25 ml) was cooled to −60° C. and thesolution of the Grignard reagent was added over 1 hour, then the mixturewas stirred for 3 hours at −60° C. Isopropanol (43.25 ml) was addeddropwise, followed by saturated aqueous ammonium chloride (86.5 ml) andbrine (43.25 ml), then the mixture warmed to room temperature. Water(173 ml) and 50% acetic acid (50 ml) to pH 6-7, followed by ethylacetate (129.7 ml). The layers were separated and the aqueous extractedwith ethyl acetate (2×129.7 ml). The combined organic layers were washedwith brine then concentrated under vacuum. The residue was stirred withhexane (216.2 ml), then the solid was filtered and washed with hexane.To the resulting solid, isopropanol (432.5 ml) was added and the mixturestirred at 45° C. for 15 minutes, then cooled to 5-10° C. and stirredfor 2 hours. The solid was filtered, washed with isopropanol and driedto give the title compound as a solid.

¹H NMR (300 MHz, CHCl3-d): δ (ppm): 1.42 (s, 9H); 2.04 (m, 1H); 2.28 (m,1H); 3.03 (m, 2H); 3.74 (s, 3H); 4.37 (m, 1H); 5.19 (b, 1H); 5.20 (s,2H); 7.02 (d, 2H); 7.11 (t, 1H); 7.17 (t, 1H); 7.33 (m, 1H); 7.48 (t,1H); 7.94 (d, 2H).

Description 27: methyl(2S)-5-{4-[(2-fluorobenzyl)oxy]phenyl}-3,4-dihydro-2H-pyrrole-2-carboxylate(D27)

Procedure 1: To a solution of methyl(2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-5-oxopentanoate(D26) (243 g) in dry DCM (2430 mL) at 0° C. was added TFA (461 mL)dropwise. The mixture was allowed to warm to room temperature andstirred for 3 hrs. Solvent and the excess TFA were removed under vacuumand the resulting dark oil was stripped with EtOAc (2×1215 mL) and leftovernight under a high vacuum. The title compound (392 g) was obtainedas a red oil and used in the following step without any furtherpurification; ¹H NMR (400 MHz, DMSO-d6) δ (ppm): 8.16 (m, 2H); 7.60 (td,1H); 7.46 (m, 1H); 7.34 (m, 2H); 7.27 (m, 2H); 5.32 (s, 2H); 5.25 (m,1H); 3.77 (s, 3H); 3.57 (m, 2H); 2.60 (m, 1H); 2.34 (m, 1H).

D27 was also obtained as follows:

Procedure 2: A solution of methyl(2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-5-oxopentanoate(D26, 46 g, 103 mmol) in DCM (437 ml) was treated dropwise withtrifluoroacetic acid (87.4 ml) at 0-5° C., then warmed to roomtemperature and stirred for 3 hours. The solution was cooled to 0-5° C.and sodium hydroxide solution added to a final pH of about 7. Theaqueous layer was separated and extracted with DCM (13 ml), then thecombined organic layers were washed with water, dried over sodiumsulphate, then concentrated under vacuum to give the title compound as asolid (33.3 g).

¹H NMR (300 MHz, CHCl3-d): δ (ppm): 2.35 (m, 2H); 2.95 (m, 1H); 3.12 (m,1H); 3.78 (s, 3H); 4.89 (dd, 1H); 5.18 (s, 2H); 7.00 (d, 2H); 7.10 (m,1H); 7.16 (m, 1H); 7.29 (m, 1H); 7.5 (t, 1H); 7.85 (d, 2H).

Description 28: Methyl(5R)-5-{4-[(2-fluorobenzyl)oxy]phenyl}-L-prolinate (D28)

Procedure 1: Methyl(2S)-5-{4-[(2-fluorobenzyl)oxy]phenyl}-3,4-dihydro-2H-pyrrole-2-carboxylate(D27) (392 g) was dissolved in EtOAc (3160 mL) in a hydrogenationreactor. 5% platinum on carbon (Engelhard code 44379, moisture contentca. 50%, 15.8 g) was added, the reactor filled with hydrogen gas to apressure of 2 atm and the reaction mixture was stirred for approximately1.5 hours. The reactor was depressurised and the spent catalyst filteredthrough Celite, washing through with EtOAc (2×500 mL, then further 200mL). Aqueous saturated NaHCO₃ solution (600 mL) was added to thefiltrate, followed by aqueous 13% w/w Na₂CO₃ solution (up to pH=9, 1000mL). The mixture was stirred for 10 minutes and phases were then allowedto separate. The aqueous phase was removed and then the organic layerwas washed once with brine (600 mL). The resulting solution wasconcentrated to dryness and the residue was purified by flashchromatography eluting with cyclohexane/ethyl acetate (1:1) to affordthe title compound (133 g); ¹H NMR (600 MHz, DMSO-d6) δ (ppm): 7.55 (dt,1H); 7.41 (m, 1H); 7.34 (m, 2H); 7.23 (m, 2H); 6.97 (m, 2H); 5.12 (s,2H); 4.09 (dd, 1H); 3.83 (dd, 1H); 3.66 (s, 3H); 2.97 (bs, 1H); 2.04 (m,2H); 1.94 (m, 1H); 1.52 (m, 1H).

D 28 was also prepared as follows:

Procedure 2: A solution of methyl(2S)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-3,4-dihydro-2H-pyrrole-2-carboxylate(D27, 34 g, 103.5 mmol) in ethyl acetate (272 ml) was placed in anautoclave and treated with trifluoroacetic acid (7.2 ml). 5% Platinum oncarbon catalyst (1.7 g) was transferred as a slurry with ethyl acetate(68 ml) and the reaction was stirred at room temperature under 50 psihydrogen pressure for 5 hours. The mixture was filtered through Hyflo,washing with ethyl acetate (272 ml), then the filtrate was washed withaq sodium carbonate solution and brine, dried over sodium sulphate, thenconcentrated under vacuum, and the residue dried to give the titlecompound as a crude oil (also containing some of the anti isomer),

1H NMR (300 MHz, CHCl3-d): δ (ppm): 1.7 (m, 1H); 2.18 (m, 4H); 3.75 (s,3H); 3.91 (m, 1H); 4.15 (m, 1H); 5.13 (s, 2H); 6.96 (d, 2H); 7.07 (m,1H); 7.15 (m, 1H); 7.30 (m, 1H); 7.38 (d, 2H); 7.5 (t, 1H).

EXAMPLES Example 1(5R)-5-(4-{[(2-Fluorophenyl)methyl]oxy}phenyl)-L-prolinamide (E1)

Procedure 1: A solution of methyl(5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinate (D28, 32.5 g,98.6 mmol) in methanol (65 ml) was cooled to 0-10° C. A solution ofammonia in methanol (ca 11.2M) was added in four portions over 11 hours(175.4 ml, 43.8 ml, 43.8 ml. 43.8 ml) then the reaction stirred at15-20° C. for 22 hours. Ammonia and methanol were removed under vacuum,then toluene (65 ml) was added and the mixture heated to 60-65° C. togive a solution, which was then concentrated under vacuum and theresidue dried at 60° C. Toluene (130 ml) and methanol (0.32 ml) wereadded to the residue and the mixture heated to 70-75° C. The resultingsolution was then cooled to 15-20° C. and stirred for 1 hour. The solidwas filtered, washed with toluene and dried at 45-50° C. to give thetitle compound (21.8 g) as a solid.

¹H NMR (500 MHz, DMSO-d6) δ (ppm): 1.39 (m, 1H); 1.84 (m, 1H); 2.04 (m,2H); 3.54 (m, 1H); 4.09 (m, 1H); 5.12 (s, 2H); 6.96 (d, 2H); 7.15 (m,1H); 7.25 (m, 2H); 7.34 (d, 2H); 7.41 (m, 2H); 7.55 (t, 1H).

E1 was also prepared as follows:

Procedure 2: Methyl (5R)-5-{4-[(2-fluorobenzyl)oxy]phenyl}-L-prolinate(D28) (127 g) was dissolved in 7N NH₃ solution in MeOH (1016 mL) and themixture was stirred at room temperature for 24 hrs. Further 7N NH₃solution in MeOH (63 mL) was added and the mixture stirred for a further15 hours. The solvent was removed under reduced pressure and MeOH (635mL) was added. The solution was evaporated to dryness and the whitesolid obtained was left under high vacuum over the weekend.

The white solid was suspended in a mixture of MTBE/Toluene 1:1 (254 mL)at 20° C. and stirred for 1 hr. The suspension was filtered and thesolid washed with MTBE (254 mL). The white solid was dried at 40° C.overnight under vacuum affording 122.4 g of material. This material wasresuspended in a mixture of MTBE/toluene 1:1 (245 mL) and stirred atroom temperature for 1 hour. The mixture was filtered and the solid waswashed with MTBE (245 mL). The white solid obtained was dried at 40° C.overnight under vacuum to give the title compound (109 g). ¹H NMR (600MHz, DMSO-d6) δ (ppm): 7.54 (td, 1H); 7.41 (m, 1H); 7.38 (m, 2H); 7.34(d, 2H); 7.24 (m, 2H); 7.13 (bs, 1H); 6.96 (d, 2H); 5.12 (s, 2H); 4.09(dd, 1H); 3.55 (dd, 1H); 3.24 (bs, 1H); 2.07 (m, 1H); 2.00 (m, 1H); 1.85(m, 1H); 1.40 (m, 1H).

Example 2 (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamidehydrochloride (E2)

Procedure 1: To a solution of 1,1-dimethylethyl(2S,5R)-2-(aminocarbonyl)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1-pyrrolidinecarboxylate(D10, 51 mg, 0.123 mmol) in a mixture of ethyl acetate (0.9 ml) andmethanol (1 ml) was added acetylchloride (28 μl, 2.5 eq) at 0° C. Themixture was shaken for 1.5 h and slowly allowed to warm to roomtemperature. After evaporating the solvent, the residue was trituratedwith diethyl ether to afford the title compound as a white solid (42 mg,quant.); Chiral HPLC: Column: chiralcel OD 10 um, 250×4.6 mm; Mobilephase: A: n-Hexane; B: Ethanol; Gradient: isocratic 30% B; Flow rate:0.8 ml/min; UV wavelength range: 200-400 nm; Analysis time: 22 min; ret.time: 12.0 min. [α]_(D)=−30.5°. MS: (ES/+) m/z: 315 [MH⁺], C18H19FN2O2requires 314; ¹H NMR (400 MHz, DMSO-d6) 8 ppm 10.19 (br. s., 1H), 8.13(br. s., 1H), 7.94 (s, 1H), 7.60-7.77 (m, 1H), 7.51 (dt, 1H), 7.43 (d,2H), 7.34-7.41 (m, 1H), 7.23 (d, 1H), 7.18 (dd, 1H), 7.05 (d, 2H), 5.13(s, 2H), 4.49-4.60 (m, 1H), 4.19-4.28 (m, 1H), 2.17-2.38 (m, 2H),2.05-2.16 (m, 1H), 1.92-2.03 (m, 1H).

Example 2 was also prepared as follows:

Procedure 2:((5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (E1, 109g) was dissolved in DCM (654 mL) and Et₂O (654 mL) was added at roomtemperature. HCl 1N in Et₂O (380.4 mL) was added dropwise at roomtemperature. The suspension was cooled to 0° C. and stirred at thistemperature for 1 hr. The solid was filtered, washed with Et₂O (2×327mL) and dried at 40° C. under vacuum overnight to afford Form 1 crystalsof the title compound (121.24 g). ¹H NMR (600 MHz, DMSO-d6) δ (ppm):10.72 (bs, 1H); 8.10 (bs, 1H); 8.08 (s, 1H); 7.72 (s, 1H); 7.56 (td,1H); 7.49 (d, 2H); 7.43 (qd, 1H); 7.25 (m, 2H); 7.10 (d, 2H); 5.17 (s,2H); 4.61 (dd, 1H); 4.30 (dd, 1H); 2.32 (m, 2H); 2.16 (m, 1H); 2.02 (m,1H).

Procedure 3:((5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (E1, 10g, 31.8 mmol) was dissolved in DCM (50 ml) and stirred with charcoal (1g), then filtered, washing with DCM (30 ml). The residue wasconcentrated under vacuum, removing about 20 ml of DCM. Ether (60 ml)was added, followed by a solution of HCl in ether (0.84N, 40 ml), andthe mixture was then stirred at 20-25° C. for 30 min, then cooled to0-5° C. and stirred for 2 hours. The solid was filtered, washed withether, then dried at room temperature to give Form 1 crystals of titlecompound (10.25 g). ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 2.04 (m, 1H);2.18 (m, 1H); 2.32 (m, 2H); 4.34 (m, 1H); 4.64 (m, 1H); 5.18 (s, 2H);7.10 (d, 2H); 7.25 (m, 2H); 7.40-7.60 (m, 4H); 7.77 (s, 1H); 8.24 (s,1H); 11.03 (b, 1H).

Procedure 4: In a round bottom flask, a solution of((5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (E1, 1.4g, 4.45 mmol) in ethylacetate (14 ml) and MeOH (2.5 ml) at 0° C. wastreated with HCl 1M in diethylether (1.1 eq, 4.89 ml). The precipitationoccurred quite soon and the mixture was stirred at 0° C. for 1 h. Themixture was then diluted with dry diethylether (10 ml) and then filteredon a Gooch filter (porosity 4, diameter 5 cm). The cake was washed onthe filter with dry diethylether (2×20 ml) and the white solid thusobtained was transferred into a round bottom flask, dried under highvacuum at 40° C. for 2 h and then at room temperature for 18 hours. Awhite solid was obtained (1.51 g) of Form 1 crystals of the titlecompound.

Procedure 5:((5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide) (E1, 25g, 79.5 mmol) was dissolved in ethyl acetate (750 ml) and stirred withcharcoal (2.5 g), then filtered, washing with ethyl acetate (125 ml). Tothe filtrate and washings, a solution of HCl in ether (1N, 103 ml), wasadded over 30 minutes at 20-25° C. and the mixture was then stirred at20-25° C. for 30 min, then cooled to 0-5° C. and stirred for 2 hours.The solid was filtered, washed with ethyl acetate (2×70 ml), then driedat room temperature to give Form 1 crystals of the title compound. (25.5g).

Unique and discriminating peaks of Form 1 of the title compound ofExample 2 have been identified and are illustrated in the table below:

Position [°2Th.] d-spacing [Å] 4.7 18.6 9.5 9.3 12.6 7.0 14.3 6.2 19.24.6 20.3 4.4 20.9 4.2 24.0 3.7 26.4 3.4

Melting point: 230° C.

Example 3 (5S)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamidehydrochloride (E3)

The title compound was synthesized (51 mg, 100%) following a similarprocedure to that described for Example 2, Procedure 1, from1,1-dimethylethyl(2S,5S)-2-(aminocarbonyl)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1-pyrrolidinecarboxylate(D15, 62 mg, 0.15 mmol); R_(t) (HPLC): 3.54 min; Chiral HPLC. Column:chiralpak AD-H 5 um, 250×4.6 mm Mobile phase: A: n-Hexane; B:Isopropanol. Gradient: isocratic 30% B. Flow rate: 0.8 ml/min. UVwavelength range: 200-400 nm. Analysis time: 15 min. ret. time: 10.4min; MS: (ES/+) m/z: 315 [MH+], C18H19FN2O2 requires 314; ¹H NMR (500MHz, DMSO-d6) δ (ppm): 9.37-9.13 (br. s., 2H), 8.01 (s, 1H), 7.68 (s,1H), 7.55 (t, 1H), 7.49 (d, 2H), 7.45-7.37 (m, 1H), 7.29-7.20 (m, 2H),7.08 (d, 2H), 5.17 (s, 2H), 4.62 (dd, 1H), 4.31 (t, 1H), 2.59-2.50 (m,1H), 2.37-2.26 (m, 1H), 2.18-2.03 (m, 1H), 2.01-1.88 (m, 1H).

Example 4 (5S)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-D-prolinamidehydrochloride (E4) Example 5(5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-D-prolinamidehydrochloride (E5)

To a solution of 1,1-dimethylethyl(2R,5S)-2-(aminocarbonyl)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1-pyrrolidinecarboxylate(D24, 145 mg, 0.37 mmol) in DCM (6 ml) was added TFA (1.5 ml) dropwiseat 0° C. The mixture was stirred for 1 h under these conditions. Afterevaporating the solvent, the resulting crude material was purified bySCX cartridge, to afford the title compounds (100 mg, 92%) as a mixtureof diastereoisomers.

The diastereoisomers were separated using chiral semipreparative HPLC:Column: chiralpak AD-H; Mobile phase: n-Hexane:Ethanol=70/30; Flow rate:13 ml/min; UV wavelength range: 225 nm; Analysis time: 25 min.

Analytical chromatographic conditions: Chiral HPLC: Column: chiralpakAD-H 5 um, 250×4.6 mm; Mobile phase: A: n-Hexane; B: Ethanol; Gradient:isocratic 30% B; Flow rate: 0.8 ml/min; UV wavelength range: 200-400 nm;Analysis time: 30 min; R_(t): 14.02 min (E4); R_(t): 16.12 min (E3)

E4 (69.5 mg): R(HPLC): 3.60 min. Chiral HPLC: Column: chiralcel OD 10um, 250×4.6 mm; Mobile phase: A: n-Hexane; B: Ethanol; Gradient:isocratic 30% B; Flow rate: 0.8 ml/min; UV wavelength range: 200-400 nm;Analysis time: 22 min; R_(t): 17.6 min. [α]_(D)=+30.7°. ¹H-NMR (400 MHz,DMSO-d₆) δ (ppm):10.19 (br.s., 1H); 8.13 (br.s., 1H); 7.94 (s, 1H);7.60-7.77 (m, 1H); 7.51 (dt, 1H); 7.43 (d, 2H); 7.34-7.41 (m, 1H); 7.23(d, 1H); 7.18 (dd, 1H); 7.05 (d, 2H); 5.13 (s, 2H); 4.49-4.60 (m, 1H);4.19-4.28 (m, 1H); 2.17-2.38 (m, 1H); 2.05-2.16 (m, 1H); 1.92-2.03 (m,1H).

E5 (32 mg): R(HPLC): 3.55 min. Chial HPLC: Column: chiralpak AD-H 5 um,250×4.6 mm; Mobile phase: A: n-Hexane; B: Isopropanol; Gradient:isocratic 30% B; Flow rate: 0.8 ml/min; UV wavelength range: 200-400 nm;Analysis time: 15 min; R_(t): 8.4 min. [α]_(D)=+24.3°. ¹H-NMR (400 MHz,DMSO-d₆) δ (ppm): 9.25 (br.s., 2H); 8.01 (s, 1H); 7.68 (s, 1H); 7.55 (t,1H); 7.49 (d, 2H); 7.37-7.45 (m, 1H); 7.20-7.29 (m, 2H); 7.08 (d, 2H);5.17 (s, 2H); 4.62 (dd, 1H); 4.31 (t, 1H); 2.50-2.59 (m, 1H); 2.26-2.37(m, 1H); 2.03-2.18 m, 1H); 1.88-2.01 (m, 1H).

Example 6 (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamidemethanesulfonate (E6)

EtOAc (6 ml) was added to(5R)-5-(4-{[(2-Fluorophenyl)methyl]oxy}phenyl)-L-prolinamide (E1, 300mg) and this was heated at 60° C. for an hour to dissolve the compound.Then methanesulfonic acid (65 μl, 1.05 eq) was added to the solution andas soon as the acid was added, the solution went cloudy. This was thenleft to temperature cycle (0-40° C.) for 2 days. The compound wasisolated by filtration as a white solid, washed with EtOAc and dried invacuo at 40° C. overweek-end to afford 335 mg of the title compound.

Melting point: 192° C.

Biological Assay

The ability of the compounds of the invention to modulate thevoltage-gated sodium channel subtype NaV 1.3 may be determined by thefollowing assay.

Cell Biology

Stable cell lines expressing hNaV1.3 channels were created bytransfecting CHO cells with the pClN5-hNav1.3 vector using thelipofectamine (Invitrogen) transfection method. pClN5 is a bicistronicvector for the creation of mammalian cell lines that predisposes allneomycin resistant cells to express recombinant protein (see Rees S.,Coote J., Stable J., Goodson S., Harris S. & Lee M. G. (1996)Biotechniques, 20, 102-112) by virtue of the recombinant cDNA beinglinked to the neomycin-selectable marker cDNA downstream of the CMVpromoter (for full details see Chen Y H, Dale T J, Romanos M A, WhitakerW R, Xie X M, Clare J J. Cloning, distribution and functional analysisof the type III sodium channel from human brain Eur J Neurosci, 2000December; 12, 4281-9). Cells were cultured in Iscove's modifiedDulbecco's medium (Invitrogen) containing, 10% fetal bovine serum, 1%L-glutamine, 1% Penicillin-Streptomycin (Invitrogen), 1% non-essentialamino acids, 2% H-T supplement and 1% G418 (Invitrogen) and maintainedat 37° C. in a humidified environment containing 5% CO2 in air. Cellswere liberated from the T175 culture flask for passage and harvestingusing Versene (Invitrogen).

Cell Preparation

Cells were grown to 60-95% confluence in a T75 flask. Cells were liftedby removing the growth media and incubating with 1.5 ml of warmed (37°C.) Versene (Invitrogen, 15040-066) for 6 min. Lifted cells weresuspended in 10 ml of PBS (Invitrogen, 14040-133). Cell suspension wasthen placed into a 10-ml centrifuge tube and centrifuged for 2 min at700 rpm. After centrifugation, the supernatant was removed and the cellpellet was resuspended in 3 ml of PBS.

Electrophysiology

Currents were recorded at room temperature (21-23° C.) using theIonWorksHT planar array electrophysiology technology (Molecular DevicesCorp.). Stimulation protocols and data acquisition were carried outusing a microcomputer (Dell Pentium 4). In order to determine planarelectrode hole resistances (Rp), a 10 mV, 160 ms potential differencewas applied across each hole. These measurements were performed beforecell addition. After cell addition a seal test was performed prior toantibiotic (amphotericin) circulation to achieve intracellular access.Leak subtraction was conducted in all experiments by applying a 160 mshyperpolarizing (10 mV) prepulse 200 ms before the test pulses tomeasure leak conductance. Test pulses stepping from the holdingpotential of −90 mV to 0 mV were applied for 20 ms and repeated 10 timesat a frequency of 10 Hz. In all experiments, the test pulse protocol wasperformed in the absence (pre-read) and presence (post-read) of acompound. Pre- and post-reads were separated by a compound additionfollowed by a 3-3.5 min incubation.

Solutions and Drugs

The intracellular solution contained the following (in mM): K-gluconate100, KCl 40 mM, MgCl2 3.2, EGTA 3, HEPES 5, adjusted to pH 7.25.Amphotericin was prepared as 30 mg/ml stock solution and diluted to afinal working concentration of 0.1 mg/ml in internal buffer solution.The external solution was Dulbecco's PBS (Invitrogen) and contained thefollowing (in mM): CaCl2 0.90, KCl 2.67, K3PO4 1.47, MgCl2 0.50, NaCl138, Na3PO4 8.10, with a pH of 7.4. Compounds were prepared in DMSO as10 mM stock solutions and subsequent 1:3 serial dilutions performed.Finally the compounds were diluted 1:100 in external solution resultingin a final DMSO concentration of 1%.

Data Analysis

The recordings were analysed and filtered using both seal resistance(>40 MD) and peak current amplitude (>200pA) in the absence of compoundto eliminate unsuitable cells from further analysis. Paired comparisonsbetween pre-drug and post-drug additions were used to determine theinhibitory effect of each compound. The concentrations of compoundsrequired to inhibit current elicited by the 1^(st) depolarising pulse by50% (tonic pIC50) were determined by fitting of the Hill equation to theconcentration response data. In addition the use-dependent inhibitoryproperties of the compounds were determined by assessing the effect ofcompounds on the 10^(th) versus 1^(st) depolarising pulse. The ratio ofthe 10^(th) over 1^(st) pulse was calculated in the absence and presenceof drug and the % use-dependent inhibition calculated. The data wasfitted using the same equation as for the tonic pIC₅₀ and theconcentration producing 15% inhibition (use-dependent pUD₁₅) calculated.

The compounds of examples 2 to 5 were tested in the above assay and gavepUD₁₅ values greater than 5.0.

1. A method of treating epilepsy in a mammal comprising administering aneffective amount of a compound of formula (I),

or a pharmaceutically acceptable salt thereof, wherein said treatingconsists of at least one selected from the following: (a) treating anestablished condition; and (b) suppressing or ameliorating symptoms. 2.A method according to claim 1 wherein the mammal is a human.
 3. A methodof treating epilepsy in a mammal comprising administering an effectiveamount of compound

or a pharmaceutically acceptable salt thereof, wherein said treatingconsists of at least one selected from the following: (a) treating anestablished condition; and (b) suppressing or ameliorating symptoms. 4.A method according to claim 3 wherein the mammal is a human.
 5. A methodof treating epilepsy in a mammal comprising administering an effectiveamount of (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamidehydrochloride, wherein said treating consists of at least one selectedfrom the following: (a) treating an established condition; and (b)suppressing or ameliorating symptoms.
 6. A method according to claim 5wherein the mammal is a human.
 7. A method of treating epilepsy in amammal comprising administering an effective amount of(5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamidehydrochloride, wherein said compound is characterized by an XRPD patternhaving characteristic peaks at the following positions: 4.7±0.15 (° 2θ),9.5±0.15 (° 2θ), 12.6±0.15 (° 2θ), 14.3±0.15 (° 2θ), 19.2±0.15 (° 2θ),20.3±0.15 (° 2θ), 20.9±0.15 (° 2θ), 24.0±0.15 (° 2θ), 26.4±0.15 (° 2θ)and wherein said treating consists of at least one selected from thefollowing: (a) treating an established condition; and (b) suppressing orameliorating symptoms.
 8. A method according to claim 7 wherein themammal is a human.